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We investigated the associations of low handgrip strength (HGS, i.e., a marker of muscular fitness) with liver fat content (LFC) and serum liver enzymes in a population‐based setting. We used data from 2700 participants (51.7% women), aged 21–90 years, from two independent cohorts of the population‐based Study of Health in Pomerania (SHIP‐START‐2 and SHIP‐TREND‐0). Cross‐sectional, multivariable adjusted regression models were performed to examine the associations of HGS with LFC, measured by magnetic resonance imaging and serum liver enzymes. We found significant inverse associations of HGS with both LFC and serum liver enzymes. Specifically, a 10‐kg lower HGS was associated with a 0.59% (95% confidence interval [CI]: 0.24–0.94; p = 0.001) higher LFC, a 0.051 µkatal/L (95% CI: 0.005–0.097; p = 0.031) higher gamma‐glutamyltransferase (GGT) concentration and a 0.010 µkatal/L (95% CI: 0.001–0.020; p = 0.023) higher aspartate aminotransferase (AST) concentration. The adjusted odds‐ratio for prevalent hepatic steatosis (defined by a MRI‐PDFF ≥5.1%) per 10‐kg lower HGS was 1.21 (95% CI: 1.04–1.40; p = 0.014). When considering only obese individuals, those with low HGS had a 1.58% (95% CI: 0.18–2.98; p = 0.027) higher mean LFC and higher chance of prevalent hepatic steatosis (adjusted OR 1.74, 95% CI: 1.15–2.62; p = 0.009) compared to individuals with high HGS. We found similar associations in individuals with overweight, but not in those with normal weight. Lower HGS was strongly associated with both higher LFC and higher serum GGT and AST concentrations. Future studies might clarify whether these findings reflect adverse effects of a sedentary lifestyle or aging on the liver. Highlights: We used magnetic resonance imaging, the most accurate and sensitive noninvasive diagnostic tool for determination of hepatic steatosisLower handgrip strength was strongly associated with both higher liver fat content and higher serum GGT and AST concentrationsEspecially overweight and obese individuals with low handgrip strength had a significant higher risk of prevalent hepatic steatosis [ABSTRACT FROM AUTHOR]

Background and Aims: Non‐alcoholic fatty liver disease (NAFLD) is associated with increased risk for cardiovascular disease. Our study investigates the contribution of NAFLD to changes in cardiac structure and function in a general population. Methods: One thousand ninety‐six adults (49.3% female) from the Study of Health in Pomerania underwent magnetic resonance imaging including cardiac and liver imaging. The presence of NAFLD by proton density fat fraction was related to left cardiac structure and function. Results were adjusted for clinical confounders using multivariable linear regression model. Results: The prevalence for NAFLD was 35.9%. In adjusted multivariable linear regression models, NAFLD was positively associated with higher left ventricular mass index (β = 0.95; 95% confidence interval (CI): 0.45; 1.45), left ventricular concentricity (β = 0.043; 95% CI: 0.031; 0.056), left ventricular end‐diastolic wall thickness (β = 0.29; 95% CI: 0.20; 0.38), left atrial end‐diastolic volume index (β = 0.67; 95% CI: 0.01; 1.32) and inversely associated with left ventricular end‐diastolic volume index (β = −0.78; 95% CI: −1.51; −0.05). When stratified by sex, we only found significant positive associations of NAFLD with left ventricular mass index, left atrial end‐diastolic volume index, left ventricular cardiac output and an inverse association with global longitudinal strain in women. In contrast, men had an inverse association with left ventricular end‐diastolic volume index and left ventricular stroke volume. Higher liver fat content was stronger associated with higher left ventricular mass index, left ventricular concentricity and left ventricular end‐diastolic wall thickness. Conclusion: NAFLD is associated with cardiac remodelling in the general population showing sex specific patterns in cardiac structure and function. [ABSTRACT FROM AUTHOR]

Background: We investigated the association between low cardiorespiratory fitness and liver fat content (LFC) in the general population. Materials and Methods: We evaluated data from 2151 adults (51.1% women) from two population‐based cohorts of the Study of Health in Pomerania (SHIP‐2 and SHIP‐TREND‐0). We analysed the cross‐sectional associations of peak oxygen uptake (VO2peak) with LFC, assessed by magnetic resonance imaging proton density fat fraction, as well as serum gamma‐glutamyltransferase (GGT) and aminotransferase concentrations by multivariable regression models. Results: We observed significant inverse associations of VO2peak with LFC and serum GGT, but not with serum aminotransferase levels. Specifically, a 1 L/min lower VO2peak was associated with a 1.09% (95% confidence interval [CI]: 0.45‐1.73; P =.002) higher LFC and a 0.18 μkatal/L (95% CI: 0.09‐0.26; P <.001) higher GGT levels. The adjusted odds ratio (OR) for the risk of prevalent hepatic steatosis (HS) by a 1 L/min decrease in VO2peak was 1.61 (95% CI: 1.22‐2.13; P =.001). Compared to subjects with high VO2peak, obese and overweight individuals with low VO2peak had 1.78% (95% CI: 0.32‐3.25; P =.017) and 0.94% (95% CI: 0.15‐1.74; P =.021) higher mean LFC, respectively. Compared to those with high VO2peak, low VO2peak was independently associated with a higher risk of prevalent HS in the obese (adjusted‐OR 2.29, 95% CI=1.48‐3.56; P <.001) and overweight (adjusted OR 1.57, 95% CI=1.16‐2.14; P =.04) groups. Conclusions: Lower VO2peak was significantly associated with greater LFC and higher serum GGT levels in a population‐based cohort of adult individuals. Our results suggest that low VO2peak might be a risk factor for HS. [ABSTRACT FROM AUTHOR]

Aims: We examined the associations between liver volume and other quantitative and qualitative markers of hepatic steatosis with all‐cause mortality in the general population. Methods: We included 2769 German middle‐aged individuals with a median follow‐up of 8.9 years (23,898 person‐years). Quantitative markers used were serum liver enzymes and FIB‐4 score, while qualitative markers of hepatic steatosis included magnetic resonance imaging (MRI) measurements of liver fat content and total liver volume. Cox proportional hazards models, adjusted for confounding factors, were undertaken to investigate the associations of liver volume and other markers of hepatic steatosis with all‐cause mortality. Results: A larger MRI‐assessed liver volume was associated with a nearly three‐fold increased risk of all‐cause mortality (Hazard Ratio = 3.16; 95% confidence interval 1.88; 5.30), independent of age, sex, body mass index, food frequency score, alcohol consumption and education level. This association was consistent in all subgroups considered (men vs. women; presence or absence of overweight/obesity, metabolic syndrome or diabetes). Higher serum liver enzyme levels and FIB‐4 score were also significantly associated with higher all‐cause mortality in the total population and in all subgroups. No independent associations were found between other quantitative and qualitative markers of hepatic steatosis and the risk of all‐cause mortality. Conclusions: We showed for the first time that larger liver volume was associated with a three‐fold increase in long‐term risk of all‐cause mortality. This association remained significant after adjustment for age, sex, alcohol consumption, obesity and other coexisting metabolic disorders. [ABSTRACT FROM AUTHOR]

Key points: Several distinct strategies produce and conserve heat to maintain the body temperature of mammals, each associated with unique physiologies, with consequences for wellness and disease susceptibilityHighly regulated properties of skin offset the total requirement for heat production We hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservationWe found that insulating mouse dermal white adipose tissue accumulates in response to environmentally and genetically induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat productionIn contrast, the body‐wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue Mammalian skin impacts metabolic efficiency system‐wide, controlling the rate of heat loss and consequent heat production. Here we compare the unique fat depots associated with mouse and human skin, to determine whether they have corresponding functions and regulation. For humans, we assay a skin‐associated fat (SAF) body‐wide depot to distinguish it from the subcutaneous fat pads characteristic of the abdomen and upper limbs. We show that the thickness of SAF is not related to general adiposity; it is much thicker (1.6‐fold) in women than men, and highly subject‐specific. We used molecular and cellular assays of β‐adrenergic‐induced lipolysis and found that dermal white adipose tissue (dWAT) in mice is resistant to lipolysis; in contrast, the body‐wide human SAF depot becomes lipolytic, generating heat in response to β‐adrenergic stimulation. In mice challenged to make more heat to maintain body temperature (either environmentally or genetically), there is a compensatory increase in thickness of dWAT: a corresponding β‐adrenergic stimulation of human skin adipose (in vivo or in explant) depletes adipocyte lipid content. We summarize the regulation of skin‐associated adipocytes by age, sex and adiposity, for both species. We conclude that the body‐wide dWAT depot of mice shows unique regulation that enables it to be deployed for heat preservation; combined with the actively lipolytic subcutaneous mammary fat pads they enable thermal defence. The adipose tissue that covers human subjects produces heat directly, providing an alternative to the brown adipose tissues. [ABSTRACT FROM AUTHOR]

Objective: This study provides a comprehensive overview of the associations of five adipokines (adiponectin, chemerin, galectin-3, leptin, and resistin) with fat deposits, behavioral risk factors, and metabolic phenotypes.Methods: Using multivariable linear and logistic regression models, cross-sectional data from 4,116 participants of the population-based Study of Health in Pomerania were analyzed.Results: Participants with obesity showed higher chemerin, galectin-3, and leptin but showed lower adiponectin concentrations. Independently of other fat compounds, liver fat content, visceral adipose tissue, and subcutaneous adipose tissue (SAT) were inversely associated with adiponectin. Independent positive associations of liver fat content and SAT with chemerin as well as of SAT with galectin-3 and leptin were observed. Physically inactive participants had higher chemerin and leptin concentrations. Smokers had higher chemerin and galectin-3 as well as lower leptin. Alcohol consumption was associated with adiponectin (positive) and resistin (inverse). All adipokines were associated with at least one lipid marker. Associations with glucose metabolism were seen for adiponectin, chemerin, galectin-3, and leptin.Conclusions: High adiponectin concentrations were related to favorable metabolic conditions, whereas high chemerin, galectin-3, and leptin were associated with an unfavorable metabolic profile. High leptin seems to be primarily indicative of obesity, whereas high adiponectin and chemerin are associated with a broader range of metabolic phenotypes. [ABSTRACT FROM AUTHOR]

Background: Iron status has been linked with impaired glucose metabolism (IGM), type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MetS), but the role of hepatic steatosis or iron overload on these associations remains uncertain. Methods: We analysed data from 2310 participants without known T2DM of the population‐based Study of Health in Pomerania (SHIP‐TREND, Germany) through logistic regression models. We tested additive and multiplicative interactions between ferritin and hepatic steatosis or iron overload. Results: Serum ferritin was positively associated with IGM (OR per 100 µg/L: 1.11 [1.01, 1.23]), T2DM (OR per 100 µg/L: 1.20 [1.06, 1.36]) and MetS (OR per 100 µg/L: 1.11 [1.02, 1.20]) in the total population as well as in participants without hepatic iron overload. However, the synergistic effect of higher ferritin concentrations and hepatic iron overload showed stronger associations with IGM and T2DM. Similarly, while ferritin was positively associated with T2DM and MetS even in the absence of hepatic steatosis, the synergistic effect of higher ferritin concentrations and hepatic steatosis showed stronger associations with IGM, T2DM and MetS. Transferrin was associated with isolated impaired glucose tolerance but not with T2DM and MetS. Conclusions: Our study suggests that ferritin may be associated with glucose metabolism disorders and MetS even in people without hepatic steatosis or iron overload. However, in individuals with higher ferritin concentrations, the presence of hepatic steatosis may indicate stronger risk for glucose metabolism disorders and MetS, while the presence of hepatic iron overload may indicate stronger risk only for glucose metabolism disorders. [ABSTRACT FROM AUTHOR]

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTRtm1HGU) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTRtm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild‐type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK‐induced trypsin activation and necrosis in acini from CFTRtm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTRtm1HGU resulted in increased INF‐γ and IL‐6, but decreased IL‐10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis—mostly via impairing duct cell function and a shift towards a pro‐inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to confirm existing assumptions about the associations of circulating chemerin with inflammatory and metabolic parameters in a large population-based study.Methods: Data of 3,986 subjects from the Study of Health in Pomerania were analyzed. Residual method was used to investigate the different associations of visceral (VAT) and subcutaneous adipose tissue (SAT) with serum chemerin levels. Multivariable regression models were applied to examine the association of chemerin with high-sensitivity C-reactive protein, fibrinogen, glucose, glycated hemoglobin, lipid profile, blood pressure, diabetes, dyslipidemia, and hypertension.Results: Positive associations with chemerin were observed for VAT and SAT with a stronger relation found for VAT. After adjustment for waist circumference, increased chemerin levels were related to higher inflammatory cytokines and glycated hemoglobin and an unfavorable lipid profile. Logistic regression revealed positive associations of chemerin with dyslipidemia [highest vs. lowest quartile: odds ratio (OR) 1.56 (95% confidence interval (CI) 1.25-1.94)] and hypertension [OR 1.31 (95% CI 1.03-1.68)].Conclusions: Chemerin levels are significantly linked to inflammation and metabolic syndrome. The majority of the detected associations persisted even after adjustment for waist circumference, suggesting that the relation of chemerin with the analyzed traits cannot be solely explained by an accumulation of adipose tissue. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the feasibility of estimating the proton-density fat fraction (PDFF) using a 7.1T magnetic resonance imaging (MRI) system and to compare the accuracy of liver fat quantification using different fitting approaches.Materials and Methods: Fourteen leptin-deficient ob/ob mice and eight intact controls were examined in a 7.1T animal scanner using a 3D six-echo chemical shift-encoded pulse sequence. Confounder-corrected PDFF was calculated using magnitude (magnitude data alone) and combined fitting (complex and magnitude data). Differences between fitting techniques were compared using Bland-Altman analysis. In addition, PDFFs derived with both reconstructions were correlated with histopathological fat content and triglyceride mass fraction using linear regression analysis.Results: The PDFFs determined with the use of both reconstructions correlated very strongly (r = 0.91). However, small mean bias between reconstructions demonstrated divergent results (3.9%; confidence interval [CI] 2.7-5.1%). For both reconstructions, there was linear correlation with histopathology (combined fitting: r = 0.61; magnitude fitting: r = 0.64) and triglyceride content (combined fitting: r = 0.79; magnitude fitting: r = 0.70).Conclusion: Liver fat quantification using the PDFF derived from MRI performed at 7.1T is feasible. PDFF has strong correlations with histopathologically determined fat and with triglyceride content. However, small differences between PDFF reconstruction techniques may impair the robustness and reliability of the biomarker at 7.1T. J. Magn. Reson. Imaging 2016;44:1425-1431. [ABSTRACT FROM AUTHOR]

Purpose To investigate flip angle (FA)-dependent T1 bias in chemical shift-encoded fat-fraction (FF) and to evaluate a strategy for correcting this bias to achieve accurate MRI-based estimates of liver fat with optimized signal-to-noise ratio (SNR). Materials and Methods Thirty-three obese patients, 14 men/19 women, aged 57.3 ± 13.9 years underwent 3 Tesla (T) liver MRI including MR-spectroscopy and four three-echo-complex chemical shift-encoded MRI sequences using different FAs (1°/3°/10°/20°). FF was estimated with R2* correction and multi-peak fat spectral modeling. The FF for each FA with and without T1 correction was compared with spectroscopy as a reference standard, using linear regression. Relative SNR of the magnitude data were assessed for each flip angle. Results The correlation between chemical shift-encoded MRI and spectroscopy was high (R2 ≍ 0.9). Without T1 correction, the agreement of both techniques showed no significant differences in slope ( PFlipAngle1° = 0.385/ PFlipAngle3° = 0.289) using low FA. High FA resulted in significant different slopes ( PFlipAngle10° = 0.016/ PFlipAngle20° = 0.014. T1 bias was successfully corrected using the T1 correction strategy (slope: PFlipAngle10° = 0.387/ PFlipAngle20° = 0.440). Additionally, the use of high FA (near the Ernst angle) improved the SNR of the magnitude data ( FA1 vs. FA3; respectively FA1 vs. FA10 P ≤ 0.001). Conclusion T1 bias is a strong confounder in the assessment of liver fat using chemical shift imaging with high FA. However, using a larger flip angle with T1 correction leads to higher SNR, and residual error after T1 correction is very small. J. Magn. Reson. Imaging 2014;40:875-883. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose To compare the accuracy of liver fat quantification using a three-echo chemical shift-encoded magnetic resonance imaging (MRI) technique without and with correction for confounders with spectroscopy (MRS) as the reference standard. Materials and Methods Fifty patients (23 women, mean age 56.6 ± 13.2 years) with fatty liver disease were enrolled. Patients underwent T2-corrected single-voxel MRS and a three-echo chemical shift-encoded gradient echo (GRE) sequence at 3.0T. MRI fat fraction (FF) was calculated without and with T2* and T1 correction and multispectral modeling of fat and compared with MRS-FF using linear regression. Results The spectroscopic range of liver fat was 0.11%-38.7%. Excellent correlation between MRS-FF and MRI-FF was observed when using T2* correction (R2 = 0.96). With use of T2* correction alone, the slope was significantly different from 1 (1.16 ± 0.03, P < 0.001) and the intercept was different from 0 (1.14% ± 0.50%, P < 0.023). This slope was significantly different than 1.0 when no T1 correction was used ( P = 0.001). When T2*, T1, and spectral complexity of fat were addressed, the results showed equivalence between fat quantification using MRI and MRS (slope: 1.02 ± 0.03, P = 0.528; intercept: 0.26% ± 0.46%, P = 0.572). Conclusion Complex three-echo chemical shift-encoded MRI is equivalent to MRS for quantifying liver fat, but only with correction for T2* decay and T1 recovery and use of spectral modeling of fat. This is necessary because T2* decay, T1 recovery, and multispectral complexity of fat are processes which may otherwise bias the measurements. J. Magn. Reson. Imaging 2014;39:1494-1501. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: To investigate R2* mapping robustness in the presence of fat using in-phase echoes, without and with spectral modeling of fat (single-peak and multipeak models, respectively), using varying numbers of echoes.Materials and Methods: Data from 88 volunteers (men/women: 52/36, ages: 55.4 ± 12.2) were randomly chosen according to magnetic resonance imaging (MRI) liver fat-fraction (%), and classified into six fat-fraction groups (1: 20 cases, 0%-<10%; 2: 20 cases, 10%-<20%; 3: 20 cases, 20%-<30%; 4: 20 cases, 30%-<40%; 5: 8 cases >40% liver fat; 6: subcutaneous fat from all cases). R2* maps obtained from five in-phase echoes (echo times: 4.8-23.8 msec) were retrospectively reconstructed using single-peak and multipeak fat modeling. R2* maps were also calculated using different numbers (2-5) of echoes.Results: Multipeak fat corrected R2* mapping is feasible from in-phase echoes, with noise performance comparable to single-peak R2* when using ≥ 4 echoes. Single-peak R2* showed poor robustness to varying echo time combinations in the presence of fat, where using few echoes resulted in large errors. These errors can be reduced using more echoes, or fully corrected using multipeak fat modeling. The mean R2* increased significantly with increasing fat-fraction when using single-peak R2* for any TE combination (P < 0.001), but did not vary when using multipeak R2* for any TE combination (P ≥ 0.158).Conclusion: R2* mapping uncorrected for spectral complexity of fat contains protocol and fat-dependent errors (lack of robustness) in tissues with high fat content. Accounting for complex fat spectrum improves robustness and accuracy of signal fitting, with modest noise performance loss. [ABSTRACT FROM AUTHOR]